U.S. Pat. No. 5,521,184 discloses a variety of N-phenyl-2-pyrimidine-amine derivatives, processes for their preparation, pharmaceutical compositions and methods of use thereof. These compounds are useful in the treatment of tumoral diseases. Among them, imatinib, 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide, is a protein-tyrosine kinase inhibitor, especially useful in the treatment of various types of cancer and for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thus, imatinib can be used for the treatment of non-maligant diseases. Imatinib is usually administered orally in the form of a suitable salt, e.g., in the form of imatinib mesylate. Imatinib mesylate is represented by the following structural formula:

Imatinib is sold by Novartis under the brand name Gleevec™ or Glivec® in the form of capsules containing imatinib mesylate equivalent to 100 mg of imatinib free base.
Imatinib mesylate can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation. Various polymorphic forms, including hydrated and solvated forms, of imatinib mesylate designated Forms α, β, H1, α2, δ, ε, I, II, F, G, H, I, K, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV, XVI and amorphous forms are apparently disclosed in U.S. Pat. No. 6,894,051 B1, U.S. Pat. No. 7,300,938 B2, PCT Patent Publication Nos. WO 2005/077933, WO 2005/095379, WO 2006/054314, WO 2006/024863, WO 2006/048890, WO 2007/023182, and WO 2007/136510.
U.S. Pat. No. 6,894,051 B1 (hereinafter referred to as the '051 patent) discloses two crystalline modifications (α-form and β-form) of imatinib mesylate. The '051 patent mentioned amorphous imatinib mesylate. However, the processes are not described for preparation of amorphous imatinib mesylate.
U.S. Pat. No. 7,300,938 B2 (hereinafter referred to as the '938 patent) discloses a crystalline (Form H1) and an amorphous hydrate (water content: 2.0-3.2 percent w/w) form of imatinib mesylate, and processes for their preparations thereof.
The pending Indian Patent Application No. 1209/MUM/2003 (hereinafter referred to as the '1209 patent application) teaches an amorphous form of imatinib mesylate having a water content of 1.5-5 percent w/w (γ-form), and a process for preparing it.
The hydrated amorphous form of imatinib mesylate disclosed in the '938 patent and the '1209 patent applications is often not very stable, hygroscopic in nature, and not ideal for the preparation of pharmaceutical composition.
PCT Publication No. 2007/136510 describes two processes for the preparation of the amorphous form of imatinib mesylate. According to the first process, amorphous imatinib mesylate is prepared by providing a solution of imatinib mesylate in a solvent selected from the group consisting of methanol, methoxyethanol, ethoxyethanol, N-methylpyrrolidone, propylene carbonate, acetonitrile, nitromethane, pyridine, dimethylsulfoxide, and mixtures thereof, and admixing the solution with an anti-solvent selected from the group consisting of ethyl acetate, butyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, methylal, ethylal and 1,3-dioxolane to obtain a precipitate of the amorphous form. According to the second process, amorphous imatinib mesylate is prepared by providing a solution of imatinib mesylate in a solvent selected from the group consisting of isobutanol, n-butanol, methoxy ethanol or ethoxyethanol, N-methylpyrrolidone, acetic acid, propylene carbonate, acetonitrile, nitromethane, pyridine, dimethylsulfoxide, and mixture thereof, and cooling the solution to a temperature of about 30° C. to about −50° C. to obtain the amorphous imatinib mesylate.
The processes for preparation of amorphous imatinib mesylate as described in the PCT Publication No. 2007/136510 A2 (hereinafter referred to as the '510 application) fail to consistently produce the amorphous imatinib mesylate. The amorphous form of imatinib mesylate obtained by the processes described in the '510 application has a water content of greater than about 1 percent w/w, does not have satisfactory purity. The amorphous imatinib mesylate is often not very stable, hygroscopic in nature, and not ideal for the preparation of pharmaceutical composition.
It has been previously disclosed that the amorphous forms in a number of drugs exhibit superior dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem. Pharm. Bull., 38, 2003 (1990)]. For some therapeutic indications, one bioavailability pattern may be favored over another. An amorphous form of cefuroxime axetil is good example of a form exhibiting higher bioavailability than the crystalline forms.
Therefore, there is a need for a highly stable anhydrous amorphous imatinib mesylate, a process for preparing it, and a pharmaceutical composition comprising it.